Interdiscip Toxicol. 2019; Vol. 12(2): 45–70.

interdisciplinary
doi: 10.2478/intox-2019-0007

Copyright © 2019 SETOX & IEPT CEM SASc.

This is an Open Access article distributed under the terms of the Creative Commons Attri-
bution-NonCommercial-NoDerivatives 4.0 License (https://creativecommons.org/licenses/
by-nc-nd/4.0).

REVIEW ARTICLE

Aluminium toxicosis: a review of

toxic actions and effects
Ikechukwu Onyebuchi IGBOKWE 1, Ephraim IGWENAGU 1, Nanacha Afifi IGBOKWE 2
1 Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Maiduguri, Maiduguri, Nigeria
2 Department Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Maiduguri, Maiduguri, Nigeria

ITX120219A01  •  Received: 22 November 2018  •  Accepted: 29 August 2019

ABSTRACT
Aluminium (Al) is frequently accessible to animal and human populations to the extent that intoxications may occur. Intake of Al is
by inhalation of aerosols or particles, ingestion of food, water and medicaments, skin contact, vaccination, dialysis and infusions.
Toxic actions of Al induce oxidative stress, immunologic alterations, genotoxicity, pro-inflammatory effect, peptide denaturation or
transformation, enzymatic dysfunction, metabolic derangement, amyloidogenesis, membrane perturbation, iron dyshomeostasis,
apoptosis, necrosis and dysplasia. The pathological conditions associated with Al toxicosis are desquamative interstitial pneumonia,
pulmonary alveolar proteinosis, granulomas, granulomatosis and fibrosis, toxic myocarditis, thrombosis and ischemic stroke, granulo-
matous enteritis, Crohn’s disease, inflammatory bowel diseases, anemia, Alzheimer’s disease, dementia, sclerosis, autism, macrophagic
myofasciitis, osteomalacia, oligospermia and infertility, hepatorenal disease, breast cancer and cyst, pancreatitis, pancreatic necrosis
and diabetes mellitus. The review provides a broad overview of Al toxicosis as a background for sustained investigations of the
toxicology of Al compounds of public health importance.

KEY WORDS: aluminium; intoxication; pathology; toxicity; toxicosis

Introduction

Aluminium (Al) is the most widely distributed metal in
the environment (Delhaize and Ryan, 1995; Ranjbar et al.,
2008; Exley and House, 2011) occurring naturally in the
trivalent state (Al+3) as silicates, oxides and hydroxides,
but may combine with other elements such as chlorine,
sulphur, fluorine, as well as form complexes with organic
matter (Jones and Bennet, 1986; Ganrot, 1986; Martin,
1992). Environmental media may be contaminated by Al
from anthropogenic sources and through the weathering
of rocks and minerals. Weathering processes on rocks
release more Al to the environment than human-related
activities (Lantzy and MacKenzie, 1979). Exposures to
Al occur in occupations associated with mining and
processing of ore, scrap metal recycling, deployment
and use of Al-containing compounds and products, and
during engagement in Al metal cutting, sawing, filing and
welding. Animals and humans living in environments
contaminated by industrial wastes may also be exposed
Correspondence address:
Ikechukwu Onyebuchi Igbokwe, DVM, MVSc, PhD, FCVSN
Faculty of Veterinary Medicine, University of Maiduguri,
Strategic Animal Research Group
P O Box 8000, Maiduguri, Nigeria
e-mail: ikeigbokwe@gmail.com; ikeigbokwe@unimaid.edu.ng
to high levels of Al (Sorgdrager et al., 1998; Vandenplas et
al., 1998; Boran et al., 2013).
Several chemical compounds with Al are in extensive
use in various products and processes associated with
human activities. These compounds are Al chloride, Al
hydroxide (alumina trihyrate), Al nitrate, Al phosphate,
Al sulfate (alum), Al potassium (potash alum), Al ammo-
nium sulfate (ammonium alum) and Al silicate (Anon,
1982; Lewis, 2001). The compounds are used in crude
oil refining and cracking of petroleum; manufacturing
of cooking utensils and foils, parchment paper, printing
ink, glass, ceramics, pottery, incandescent filaments,
fireworks, explosives, photographic flashlight, electric
insulators, cement, paints and varnishes, fumigants and
pesticides, lubricants, detergents, cosmetics, pharma-
ceuticals (drugs), vaccines, as well as in water treatment
and purification, treating sewage and fur, tanning leather,
waterproofing clothes and concretes, industrial filtration,
hemodialysis, measuring radiation exposure, in products
as flame retardant and fireproofing, anticorrosion agent,
food additives to prevent caking as well as components
of baking powders and colorants (Anon, 1982, 2008a;
Malakoff, 2000; Lewis, 2001; Soni et al., 2001; Saiyed and
Yokel, 2005).
The Al ion has no physiological role in metabolic
processes (Exley and House, 2011) but it can be a metallic
46 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
toxicant to humans and animals (Becaria et al., 2002)
when there is high body burden of the metal after natural
or unnatural exposure (Exley, 2013). Al was considered
unsafe to humans after the discovery of increased levels
of Al in brain tissues of patients with encephalopathy,
having been exposed to Al accumulation through dialysis
(Alfrey and Solomons, 1976). Toxicosis due to Al accumu-
lation in mammalian tissues was associated with various
pathologic effects (Wills and Savory, 1983; Kaiser et al.,
1984; Boyce et al., 1986; Drüeke et al., 1986; Hewitt et al.,
1990; Bushinsky et al., 1995; Reinke et al., 2003; Abubakar
et al., 2004; Bogdanović et al., 2008; Yousef and Salama,
2009; Khattab et al., 2010; Blaylock, 2012; Buraimoh and
Ojo, 2013; Sumathi et al., 2013). Recent reviews on toxic
effects of Al covered reproductive toxicity (Mouro et al.,
2017), pulmonary lesions (Kongerud and Søyseth, 2014;
Taiwo, 2014), impact on the breast (Darbre, 2016), bone
abnormalities (Chappard et al., 2016; Klein, 2019), immu-
notoxity (Zhu et al., 2014a) and neurologic disorders
(Colomina and Peris-Sampedro, 2017; Morris et al., 2017).
This review is an abridged and global overview of toxic
effects of Al and its compounds, covering some relevant
aspects of exposure and updated systemic toxicosis in
humans and animals, relevant as background for prospec-
tive toxicopathologic studies.
Literature search justification and methods
The initial goal in our study group was to explore the
role of the ubiquitous Al ion in erythrocyte membrane
dysfunction (Igbokwe, 2016) and metabolic dysregulation
(Igwenagu, 2017). With the preliminary literature search
starting in 2013 and looking backwards in time, research
publications revealed a myriad of toxic actions of Al caus-
ing pathological conditions. Several narrative literature
reviews, referred to in the introductory section, were
Figure 1. Major themes for the literature search on aluminium toxicosis.
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discovered to have focused on Al toxicity of one system
of the body in each review, covering the scope of nervous,
reproductive, respiratory, mammary, skeletal and immune
tissue toxicities. One review addressed the toxicities in
bone, hematopoietic tissue and kidney (Jeffrey et al., 1996)
and another summarized the physiological alterations in
the musculoskeletal, respiratory, cardiovascular, hepatobi-
liary, endocrine, urinary and reproductive systems(Nayak,
2000). Thus the question raised was whether Al toxicosis,
as a disease entity, existed in the literature with cur-
rent research information. The literature search for Al
toxicosis as a narrative review (Green et al., 2006) with
a broad thematic approach was unproductive and this
observation justified the need for the current review.
Toxicosis associated with Al exposure is the pathologi-
cal condition or disease caused by the toxic actions of Al
and its compounds. The literature search was intended
to collate, synthesize and integrate the published reports
on the subject matter without meta-analysis and critical
evaluation of published data. For this review, the major
themes for the literature search under the title included
exposure modalities, toxic actions and effects in cells,
tissues and systems of the body (Figure 1). These themes
provided the key words and phrases for the internet search.
The initial search platform was usually GOOGLE.COM
with the linked GOOGLE SCHOLAR helping to search
related articles. Subsequently, the search was extended to
MEDLINE, PUBMED, PMC Europe, RESEARCHGATE,
SCOPUS, SCIENCEDIRECT, SAGE, TANDFONLINE
and SPRINGERLINK. On each platform, an article that
was found could also have links to related articles and
these links were followed to enrich the search outcomes.
Every article was read as an abstract or full article after
downloading to the literature bank. At this stage, “back-
ward search” based on references of read articles could
be done and “forward search” was required when new
themes emerged that needed further exploration. The

integration of the literature search processes are illus-
trated in Figure 2. Occasionally, article request options
were used to obtain restricted publications and the articles
were received from authors. The literature collated from
the search was read for content comprehension. The body
of knowledge was summarized and narrated after cogni-
tive reflection and integration to represent the current
knowledge of the literature on Al toxicosis. The articles
with thematic contents were included for the review when
they were published in journals with reputable standing.
The contents of the excluded articles were peripheral to
the themes under review.
Exposure to aluminium
Aluminium intake
Aluminium in the air
The largest source of airborne Al-containing particles
is the dust from soil and rocks (Lee and Von Lehmden,
1973; Sorenson et al., 1974). Human activities, such as
mining and agriculture, contribute to the dust in winds
(Eisenreich, 1980; Filipek et al., 1987). About 13% of
atmospheric Al is attributed to anthropogenic emissions
(Lantzy and MacKenzie, 1979). The major anthropogenic
sources of Al-containing particulate matter include coal
combustion, Al production, iron and steel foundries,
brass and bronze refineries, motor vehicle emissions and
other industrial activities such as smelting, filing, sawing,
welding of Al metals (Lee and Von Lehmden, 1973; Ondov
et al., 1982; Que Hee et al., 1982). Cigarette smoke may
contribute to the concentration of Al in the air (Exley
et al., 2006; Kazi et al., 2009; Pappas, 2011; Afridi et al.,
2015). The air containing Al particles or droplets becomes
the source of Al in inhaled aerosols.
Aluminium in drinking water
Al occurs ubiquitously in natural waters due to weather-
ing of Al-containing rocks and minerals and mobilization
from terrestrial to aquatic environment (Campbell et al.,
1992). This mobilization of Al is often seasonal in nature
and is associated with pH depressions (acidification)
occurring during the spring snow melt or associated with
erosion from specific storm events (Rosseland et al., 1990;
Nelson and Campbell, 1991; Campbell et al., 1992). Al
concentrations in surface waters can be increased directly
or indirectly by human activities through industrial and
municipal discharges, surface run-off, tributary inflow,
groundwater seepage, and wet and dry atmospheric depo-
sition (Eisenreich, 1980). Industrial release of Al in waste
materials into surface waters from processing and manu-
facturing facilities could be toxic to aquatic life (Filipek
et al., 1987; Trieff et al., 1995; His et al., 1996; Gensemer
and Playle, 1999). Acidic drainage from mines or acid
rain may cause an increase in the dissolved Al content
of the surrounding water bodies (Cronan and Schofield,
1979; Filipek et al., 1987). The use of Al compounds as
coagulating agents in the treatment of water for drinking
could increase its Al content (Qureshi and Malmberg,
Copyright © 2019 SETOX & Institute of Experimental Pharmacology and Toxicology, CEM SASc.
Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 47
Full-text also available online on PubMed Central
Literature
Search: HOW
Research Articles:
Backward
Primary (original research)
Forward
Search Search
Secondary (review)
GOOGLE.COM
MEDLINE
PUBMED
PMC Europe
RESEARCHGATE
SCOPUS
SCIENCEDIRECT
SAGE
TANDFONLINE
SPRINGERLINK
Figure 2. Integrated literature search process.
1985; Henshaw et al., 1993; Cech and Montera, 2000). In
pure water, Al has a minimum solubility in the pH range
of 5.5–6.0 and concentrations of dissolved Al increase
at higher or lower pH values (Browne et al., 1990). The
source of water for human and animal consumption and
the purification process involved may influence the Al
content of drinking water as source of exposure.
Aluminium in food
Al is present in foods naturally or from the use of
Al-containing food additives (Sepe et al., 2001; Flaten,
2002; Hayacibara et al., 2004; Yokel et al., 2008). The
concentrations in foods and beverages vary widely,
depending upon the food product, the type of processing
used, and the geographical areas in which the food crops
are grown (Sorenson et al., 1974; Pennington and Schoen,
1995). The foods highest in Al are those that contain Al
additives (Pennington, 1988; Greger, 1992; Saiyed and
Yokel, 2005; Yokel and Florence, 2006; Yokel, 2012). The
use of Al cookware, utensils and wrappings can increase
the amount of Al in food (Liukkonen-Lilja and Piepponen
1992; Pennington and Schoen, 1995). The migration of Al
from cookware into food increases with the acidity of the
food and the duration of exposure (Valkonen and Aitio,
1997; Lin et al. 1997). Al was also reported to migrate into
fish grilled on Al foil and the migration of Al into foods
appeared to be dependent on factors such as temperature,
duration of cooking, the composition and pH of the food,
and the presence of other substances like organic acids
and salts (Ranau et al., 2001). Foods found to be naturally
high in Al include potatoes, spinach and tea (Pennington
and Schoen, 1995; Stahl et al., 2011). Processed dairy
products and flour may be high in Al if they contain
Al-based food additives (Pennington and Schoen, 1995).
48 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe

Daily intakes of Al in humans from food range from 3.4
to 9 mg/day (Pennington and Schoen, 1995; Biego et al.,
1998; Yang et al., 2014). It is unlikely that Al-containing
food additives are intentionally added to the diets of live-
stock and pets yet, Al contamination of some additives
used in livestock and pet food is possible (Burgoin, 1992).
Thus Al contents of harvested food products, processed
foods, and cooked, baked or grilled foods may be sources
of Al exposure.
Aluminium in pharmaceuticals and agrochemicals
The route of intoxications with pharmaceuticals and agro-
chemical sources may be through inhalation of aerosols,
ingestion of medications or by parenteral administration.
Humans and animals are exposed to Al-containing
medications such as phosphate binders, antacids, buffered
analgesics, antidiarrheal and antiulcer drugs (Lione, 1983,
1985; Yokel and McNamara, 2001; Krewski et al., 2007).
Various intravenously administered pharmaceutical
products were reported to contain 684–5977 µg/g of Al
(Sedman et al., 1985). Many antacids contain 104–208 mg
of Al per tablet, capsule or 5 ml of suspension (Zhou
and Yokel, 2005). The use of other consumer items
such as dentifrices, disinfectants, fumigants, pesticides,
anti-perspirants and some cosmetics are sources of Al
exposure (Lewis, 2001; Pineau et al., 2014). Al hydroxide,
Al phosphate, Al potassium sulfate (alum), and Al silicate
(zeolite) are used in the preparation of a number of vac-
cines to adsorb antigenic components and to serve as
adjuvant that enhance immune response (Lione, 1985;
Tomljenovic and Shaw, 2011; Issa et al., 2014). Adjuvant
as a source of Al during vaccinations has been receiving
attention in research (Malakoff, 2000; Keith et al., 2002;
Mitkus et al., 2011; Glanz et al., 2015) and it is presumed
that there could be mistakes in adjusting Al content of
vaccines to body weights of neonates who stand the risk
of Al toxicity from vaccines (Lyons-Weiler and Ricketson,
2018). More Al was absorbed into blood by rabbits after
intramuscular injection with adjuvant containing Al
phosphate compared to Al hydroxide (Hem, 2002). It is
unlikely that parenteral Al administrations are a major
source of Al exposure to livestock or pets (Issa et al., 2014).

Aluminium Compounds

Aerosol Infusions
Vaccines
Water Dialysate
Food
INHALATION Medicaments

LUNG
INGESTION PARENTERAL TREATMENT
?

Decreased by Increasde by
ABSORPTION
• Iron overload • Chronic kidney disease
• Dietary • Deficiency of Ca & Mg ions
- Phytates • Dietary
- Polyphenols - Citrate
- Phosphate
BLOOD CIRCULATION
- Maltol
- Silicon - Lactate
- Sialic acid - Fluoride

Urine
Bile
Faeces EXCRETION TISSUE ACCUMULATION
Sweat
Hairs
Nail Increased by chelators
Sebum
Semen
• Deferoxamine
Milk • Malic acid
• Citric acid
• Malonic acid
• Oxalic acid
• Succinic acid

Figure 3. Factors affecting tissue accumulation of aluminium and development of toxicosis.

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Food or water for livestock could be contaminated with Al
when Al sulfate and zeolite are applied to litter and waste
lagoons to reduce phosphorus loss from lands fertilized
with the wastes and to reduce ammonia fumes in facili-
ties (Moore et al., 1999; Moore et al., 2000; Codling et al.,
2002). Alum has also been added to dairy slurry to reduce
ammonia emissions (Lefcourt and Mesinger, 2001). Thus,
this section indicates that Al exposure can arise when
certain pharmaceutical products are administered orally
or parenterally to individuals or when agrochemicals
contaminate food/feed and water taken by individuals or
those in close proximity inhale aerosols from agrochemi-
cal fumigants and sprays.
Absorption, distribution and elimination of aluminium
The dynamic chain of Al intake, absorption and elimi-
nation determines the level of tissue accumulation and
development of toxicosis (Figure 3). Inhalation and inges-
tion (via food and water) are the two main routes through
which Al gets into the body (Alfrey, 1980; Teraoka, 1981;
Jouhanneau et al., 1997). Following inhalation, Al com-
pounds are deposited in the lungs (Christie et al., 1963;
Stone et al., 1979; Thomson et al., 1986). The lungs con-
tinually receive Al mostly as particles of Al silicates and
other poorly soluble compounds (Thomson et al., 1986).
The concentration of Al in the lungs tends to increase
with age and may result in respiratory anomalies where
the Al is localized (Alfrey, 1980; Teraoka, 1981; Taiwo,
2014). There is no available evidence in literature that
particulate or soluble Al gets into the blood circulation
from the lungs to be subsequently distributed to other
organs of the body.
Gastrointestinal absorption, after ingestion, is the
main route through which Al is systemically accumulated
in animals and humans, and absorption occurs largely in
the duodenum (Feinroth et al., 1984; Steinhausen et al.,
2004). The absorption of Al is usually low and varied when
compared with the amount ingested (Kawahara et al.,
2007). The uptake of Al through gastrointestinal pathway
is complex and is influenced by various factors including
individual differences, age, pH, stomach contents and
type of Al compound (Priest et al., 1996). Al absorption
from water intake (about 0.3%) is greater than from food
(about 0.1%) (Martyn et al., 1989; Steinhausen et al., 2004;
Anon, 2008b; Zhou et al., 2008).This was attributed to
organic ligands in foods such as phytates and polyphenols
that were suggested to form complexes with Al ion and
inhibit its absorption (Reto et al., 2007). Absorption of
Al via the gastrointestinal tract can be enhanced in the
presence of citrate, maltol, lactate and fluoride in water
or food, and during chronic renal diseases, while the
absorption is reduced in individuals with iron overload,
or when ingested with phosphate, silicon, polyphenols
and sialic acid (Brown et al., 1987; Edwardson et al.,
1993; Anon, 2008c; Zhou et al., 2008). However, there is
complete Al uptake from parenteral fluids and vaccines
with subsequent distribution to various parts of the body
(Tomljenovic and Shaw, 2011).
Copyright © 2019 SETOX & Institute of Experimental Pharmacology and Toxicology, CEM SASc.
Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 49
Full-text also available online on PubMed Central
About 90% of the Al circulating in the blood is trans-
ported bound to transferrin (iron-transporter protein),
while the rest of Al binds to albumin and citrate in
the blood (Day et al., 1991; Harris and Messori, 2002;
Hemadi et al., 2003; Chen et al., 2010). Cellular uptake
of Al in tissues is relatively slow and is presumed to
be mediated by endocytosis and intracellular transfer
of the Al bound to transferrin (Hemadi et al., 2003).
However, Al-transferrin complex may not bind to the
transferrin-receptor (Hemadi et al., 2003; Sakajiri et al.,
2010), indicating the existence of an alternative mecha-
nism of cellular uptake of Al (DeVoto and Yokel, 1994;
Anon, 2011). The total body burden of Al in healthy
humans has been reported to be approximately 30–50
mg/kg body weight and normal levels of Al in serum are
approximately 1–3μg/L (Krewski et al., 2007). The mean
serum Al level in 44 non-exposed persons who did not
use antacids was reported to be 1.6 μg/L (Valkonen and
Aitio, 1997) and Chen et al. (2010) reported that values
in hemodialysis patients were ten-fold higher than the
values in unexposed individuals. About one-half of the
total body Al is in the skeleton, and the levels in human
bone tissue range from 5 to 10 mg/kg (Anon, 2008c). Al
has also been found in human skin, lower gastrointes-
tinal tract, lymph nodes, adrenals, parathyroid glands,
and in most soft tissue organs (Anon, 2008b). In rats,
accumulation of Al after oral exposure was higher in the
spleen, liver, bone, and kidneys than in the brain, muscle,
heart, or lungs (Anon, 2008b). It has also been reported
that Al can reach the placenta and fetus and to some
extent distribute to the milk of lactating mothers (Anon,
2008b). Al levels increase with age in tissues and organs
(bone, muscle, lung, liver, and kidney) of experimental
animals (Krewski et al., 2007). Moreover, Al has been
shown to rapidly enter the brain, extracellular fluid and
the cerebrospinal fluid, with smaller concentrations in
these organs than in the blood (Martin, 1992; Krewski et
al., 2007). The iron status is negatively correlated with
Al accumulation in tissues and animal experiments
have shown that calcium and magnesium deficiency may
contribute to accumulation of Al in the brain and bone
(Anon, 2011).
The Al ion in blood circulation is eliminated primarily
by the kidneys (about 95%) in the urine, presumably as
Al citrate (Shirley and Lote, 2005; Krewski et al., 2007;
Anon, 2008c). Tissue accumulation of Al is reduced by
citrates and fluorides through renal excretion when the
transferrin-Al binding capacity of the blood is exceeded
(Anon, 2008b). Al is also excreted in the milk, bile, feces,
sweat, hairs, nails, sebum and semen (Gorsky et al.,
1979; Greger and Sutherland, 1997; Exley, 2013). Urinary
excretion of Al is enhanced by chemical chelators such as
deferoxamine and malic, malonic, citric, oxalic and suc-
cinic acids, as reviewed in the later section on treatment
of Al in this document. On the whole, it is noted that Al
accumulation, which is responsible for Al toxicosis, is
enhanced by exposure to Al and its continuous intake,
as well as increased intestinal absorption and decreased
excretion of the metal (Figure 3).
50 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
Toxic actions of aluminium
The toxic actions of Al responsible for the toxic effects
of the toxicities are diverse and capable of causing a
multifaceted systemic toxicosis. These toxic actions are
summarized in Table 1. The molecular targets of action
generate outcomes in the cell and disrupt cellular homeo-
stasis with consequences that lead to lesions in the cell
(Figure 4), which are responsible for systemic toxicosis
associated with structural and functional abnormalities
of organs.
Toxic effects of Al arise mainly from its pro-oxidant
activity which results in oxidative stress, free radical
attack and oxidation of cellular proteins and lipids (Exley,
2013). Protein polypeptides are transformed to second-
ary structures when Al ions interact with them through
oxygen-containing amino acids, side chains and protein
backbone leading to ultimate denaturation (Mujika et al.,
2018) or conformational or structural alteration (Exley et
al., 1993; Zatta et al., 2005; Exley, 2006) as in β-amyloid.
Table 1. Toxic actions associated with aluminium exposure.
Toxic action or effect
Oxidative stress, lipid peroxidation
Pro-inflammatory: organ inflammation in lung, intestine, heart, and testis
Immunosupression: induces lymphocyte apoptosis and dysfunction,
inhibits lymphocyte proliferation, causes macrophage dysfunction
Protein denaturation and transformation
Enzymatic stimulation or inhibition
Metabolic impairment: impairs glycolysis and Kreb’s
cycle; promotes lipid and protein oxidation
Genotoxicity: reduced cell proliferation and differentiation, dysneurogenesis
Amyloidogenic and anti-amyloidolytic
Acts as metalloestrogen, promotes prolifera-
tion and migration of breast cancer cells
Induces teratogenesis causing foetal and neonatal defects
Disrupts mineral metabolism of Fe, P, Ca, Zn, Cu by alter-
ing intestinal absorption and cellular uptake
Induces apoptosis, eryptosis, tissue necrosis
Disrupts cell membrane permeability and receptor function,
increases osmotic fragility, inhibits membrane ATPases
Endocrine disruption: parathyroid hormone, testosterone, lutein-
izing hormone, follicle stimulating hormone, estradiol, nor-
epinephrine, cortisol, thyroid hormone, insulin
Inhibits cartilage formation
Inhibits bone formation and mineralization by increasing osteo-
clastic activity and reducing osteoblastic activity
Induces hypertension (systolic and arterial)
Causes ischaemic stroke and thrombosis
Induces contact allergy
Inhibits the biological function of vitamin D in the
intestine linked to calcium absorption
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The aggregation and precipitation of β-amyloid is trig-
gered and potentiated by Al exposure which is associated
with Alzheimer’s disease (Bondy and Truong, 1999; Zatta
et al., 2005; Exley, 2006) and this phenomenon may be
responsible for neuritic plaque deposition, neuronal
death and dysneurogenesis. Fibrillation and aggregation
of human islet amyloid polypeptide hormone (amylin)
was stimulated by Al exposure leading to formation of
β-pleated sheet structure (Mirhashemi and Aarabi, 2011;
Mirhashemi and Shahabaddin, 2011; Xu et al., 2016),
which may predispose pancreatic β-cell to damage. The
proteolytic degradation of the amyloid peptides is also
prevented by Al, thereby enhancing the accumulation of
the amyloid (Sakamoto et al., 2006). Extracellular sur-
faces and intracellular ligands may likely associate with
Al to induce inhibitory or stimulatory effects (Exley and
Birchall, 1992). Interaction of Al with metabolic and other
enzymes causes inhibition or activation of the enzymes
(Hofstetter et al., 1987; Xu et al., 1990; Exley et al., 1994;
Zatta et al., 1999, 2000; Yang et al., 2003; Mailloux et al.,
Selected references
Kattab et al., 2010; Exley, 2013; Abd-Elhady et al., 2013;
Zhang et al., 2016; Yang et al., 2018; Yu et al., 2019
Fogarty et al., 1998; Verma et al., 2007; Lerner, 2007; Exley,
2013; Taiwo, 2014; de Chambrun et al., 2014; Gherardi et al.,
2016; Martinez et al., 2017; Hangouche et al., 2017
Nordal and Dahl, 1988; Kammalov et al., 2011; She et al., 2012; Zhu
et al., 2014; Zhuang et al., 2016; Xu et al., 2018; Yu et al., 2019
Exley et al., 2006; Mujika et al., 2018
Ohsaka and Nomura, 2016
Xu et al 1990; Mailloux et al., 2006
Nam et al., 2014
Sakamoto et al., 2006; Xu et al., 2016
Bakir and Darbre, 2015; Darbre, 2016
Malekshah et al., 2005; Wang et al., 2012; El Mazoudy and Bekhet, 2016
Jeffery et al., 1996; Contini, 2007; Kell, 2009; Fu et al., 2014; Zhu et al., 2014
Niemoeller et al., 2006; Xu et al., 2018; Yang et al., 2018; Yu et al., 2019
Fu et al., 2014; Zhang et al., 2016; Sun et al., 2018; Gomes et al., 2019
Díaz-Corte et al., 2001; Chinoy and Patel, 2001; Gonzelez-Suerez et al., 2005;
Shahraki et al., 2008; Orihuela, 2011; Sun et al., 2011; Muselin et al., 2016;
Zhuang et al., 2016; Mouro et al., 2018; Wei et al., 2018 Gomes et al., 2019
Zhang et al., 2017
Cox and Dunn, 2001; Li et al., 2012; Cao et al., 2016; Song et al., 2016; Sun et
al., 2016; Yang et al., 2016; Huang et al., 2017; Yang et al., 2018; Xu et al., 2018
Zhang et al., 2016
Abedini et al., 2014
Netterlid et al., 2013
Dunn et al., 1995

Figure 4. Cellular pathology in the systemic toxicosis of aluminium.
Figure 5. Metabolic abnormalities in aluminium toxicosis.
2006; Sushma et al., 2007; Ohsaka and Nomura, 2016). Al
binds to the phosphate groups of nucleotide such as ade-
nosine triphosphate (ATP) and affects energy metabolism
(Kawahara et al., 2007). Exposure of hepatocytes to Al
impedes ATP production, inhibits glycolysis, impairs the
function of tricarboxylic acid (Kreb’s) cycle and promotes
lipid and protein oxidation (Xu et al., 1990; Mailloux et al.,
2006) with a metabolic shift to lipogenesis in tissues (Han
et al., 2013). These metabolic perturbations (Figure 5)
may be responsible for the reports of body weight loss and
decreased production performance (like egg production)
in animals exposed to Al (Wisser et al., 1990; Capdevielle
and Scanes, 1995; Li et al., 2015).
Al exposure can cause the disruption of iron homeo-
stasis leading to iron overload (Ward et al., 2001; Contini
et al., 2007). Oxidative stress and injury, mediated by iron,
seems to be facilitated by Al (Xiea et al., 1996). Elevated
concentrations of cellular iron can enhance oxidative
damage to the cell and are linked to the pathogenesis
of neurodegenerative disorders (Jang and Surh, 2002;
Toyokuni, 2002; Adzersen et al., 2003; Deugnier, 2003;
Ng, 2004). Iron overload due to Al exposure has been
shown to result in increased lipid peroxidation, DNA
lesions, and apoptosis induced by reactive oxygen species
(Bacon et al., 1983; Oteiza, 1994; Kell, 2009). Apoptosis
of erythrocytes (eryptosis), lymphocytes and osteoblasts
is also stimulated by Al ions (Niemoeller et al., 2006; Li
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Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 51
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et al., 2012; Xu et al., 2018; Yang et al., 2018; Yu et al.,
2019). The oxidative injury was reported to activate the
JNK apoptotic pathway in ostoblasts (Yang et al., 2018).
In culture, Al induced apoptosis of osteoblasts by inhibit-
ing apoptotic Bcl-2 protein expression and increasing the
expression of pro-apoptotic Bax, Bak and Bim proteins
(Xu et al., 2018). Al may decrease ferritin synthesis and
increase the expression of transferrin receptors, thereby
disrupting the normal synthesis of transferrin receptors
with ferritin creating increased free iron levels in the
cell, resulting in an increase of oxidative damage via the
fenton reaction (Yamanaka et al., 1999). The activities of
superoxide dismutase (SOD), catalase (CAT), glutathione
peroxidase (GPx) and glutathione (GSH) are affected
by Al exposure because of oxidative stress (Oteiza et
al., 1993a; Julka and Gill, 1996; Campbell et al., 1999).
Abnormal increases in levels of malondealdehyde (MDA)
and thiobarbituric acid reactive substances (TBARS) were
reported along with decreased levels of antioxidants such
as GSH, GPx, SOD, and CAT in tissue homogenates of rats
exposed to Al (Anane and Creppy, 2001; Gonzalez et al.,
2007; Newairy et al., 2009; Khattab et al., 2010; Bai et al.,
2012; Exley, 2013; Abd-Elhady et al., 2013; Zhang et al.,
2016; Yu et al., 2019).
Mutagenesis and alteration of gene function may arise
from the toxic action of Al with changes in transcrip-
tional expressions (Exley, 2013). Somatic and germinal
52 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
genetoxicity in mice exposed to Al was associated with
chromosomal aberrations and depression of mitosis
(D’Souza et al., 2014). Neuronal gene expression is influ-
enced by the binding of Al to DNA (Lukiw et al., 1998)
predisposing cells to or causing genotoxicity (Pogue and
Lukiw, 2016) and thus Al exposure may lead to reduction
of cell proliferation and differentiation (Nam et al., 2014,
2016; Sun et al., 2015; Cao et al., 2016; Li et al., 2016; Yang
et al., 2016; Sun et al., 2016, 2017; Huang et al., 2017).
Neurogenesis was impaired by Al toxicity (Nam et al.,
2014, 2016). Osteoblastic proliferation and differentiation
were inhibited by Al when there was downregulation and
inhibition of Wnt/β-catenin signaling pathway (Sun et
al., 2015; Cao et al., 2016; Huang et al., 2017; Sun et al.,
2017). Osteoblast differentiation was also inhibited by
Al through the inhibition of BMP-2 signaling pathway
(Yang et al., 2016). In addition, osteoblast mineralization
in vitro was inhibited by Al-induced decline in trans-
forming growth factor (TGF)-β1 expression and action,
and upregulation of Smad7 expression (Sun et al., 2016)
along with decreased protein expressions of osteopontin,
osteocalcin and osteosialoprotein (Song et al., 2017). The
mineralization of bone is impaired by decreased calcium
absorption (Orihuela, 2007), because Al inhibits the syn-
thesis of calbindin, a calcium-binding protein involved
in transcellular transport of calcium in enterocytes and
inhibits the stimulation of synthesis of osteocalcin (the
bone matrix protein) in osteoblasts by vitamin D via cel-
lular unresponsiveness (Fanti et al., 1992; Jeffery et al.,
1996; Cox and Dunn, 2001). The expression of cartilage
stimulating growth factors, TGF-β1 and BMP-2, were
inhibited by Al, thereby suppressing cartilage growth
and disrupting cartilage structure (Zhang et al., 2017).
The effects of Al on growth manifested in developmental
abnormalities of fetuses due to teratogenesis in pregnant
individuals (Malekshah et al., 2005; Wang et al., 2012; El
Mazoudy and Bekhet, 2016; Yassa et al., 2017).
The proliferative and migratory characteristics of the
human breast cancer cell may be affected by Al when it
acts as a metalloestrogen or increases the intracellular
Figure 6. Inflammatory conditions in aluminium toxicosis.
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
secretion of matrix metalloproteinase (MMP9) and levels
of activated MMP14 that are involved in migratory and
invasive properties of cancerous cells, thereby influencing
the metastatic process (Darbre et al., 2013a, b; Bakir and
Darbre, 2015; Darbre, 2016). It is unclear whether Al has
the capacity to initiate and promote any other carcino-
genic process apart from the indirect evidence provided
above with regard to breast cancer.
Pro-inflammatory actions of Al have been reported in
various tissues (Fogarty et al., 1998; Verma et al., 2007;
Lerner, 2007; Exley, 2013; Taiwo, 2014; de Chambrun
et al., 2014; Gherardi et al., 2016; Martinez et al., 2017;
Hangouche et al., 2017). It is triggered by Al-induced
oxidative stress and free radical production (Milnerowicz
et al., 2015). Exposure to Al increased pro-inflammatory
cytokine (interleukin-1β and tumor necrosis factor alpha)
levels (Jangra et al., 2015) and elevated gene expression of
tumor necrosis factor alpha (TNFalpha) and macrophage
inflammatory protein-1alpha (MIP-1alpha)  in concen-
tration-dependent manner (Johnson and Sharma, 2003).
Genes that encode pro-inflammatory signaling elements
were significantly up-regulated by Al (Lukiw et al., 2005).
These cytokines that are released due to Al exposure can
recruit leukocytes, which secrete more pro-inflammatory
cytokines and other chemokines, to exacerbate the
inflammation (Milnerowicz et al., 2015). The inflamma-
tion can be a chronic granulomatous type (Chen et al.,
1978; de Vuyst et al., 1987; Forgarty et al., 1998; Gherardi
and Authier, 2012) and Al has been reported to cause
granuloma formation in vitro (de Chambrun et al., 2014).
Chronic exposure of mice (5 months) to Al sulfate in
drinking water elicited time-dependent systemic inflam-
mation characterized by increased serum  interleukin-6
(IL-6) and tumor necrosis factor alpha (TNFα), C-reactive
protein (CRP) and a triad of pro-inflammatory microR-
NAs (miRNA-9, miRNA-125b and miRNA-146a) and
the biomarkers of inflammation   indicated progressive
chronic inflammation in the exposed animals (Pogue et
al., 2017). The inflammatory conditions associated with
Al exposure are summarized in Figure 6.
 Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 53
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Table 2. Effects of aluminium exposure on endocrine secretions in animals.

Hormone Animal/human Increase Decrease Normal Reference
Plasma growth hormone Duckling + Capdevielle et al., 1995
Plasma insulin-like growth Duckling + Capdevielle et al., 1995
factor 1
Plasma cortisol Rat + Vasanthan and Joshi, 2018
Blood norepinephrine Rat + Zhuang et al., 2016
Serum estradiol Mice + Chinoy and Patel, 2001
Serum testosterone Gerbil + Reza and Palan, 2006; Gomes et al., 2019
(Meriones unguiculatus)
Rat + Shahraki et al., 2008; Sun et al., 2011; Muselin et al., 2016;
Mouro et al., 2018
Serum luteinizing hormone Rat + Shahraki et al., 2008; Sun et al., 2011; Muselin et al., 2016
Rat + Reza and Palan, 2006
Serum follicule stimulating Rat + Reza and Palan, 2006; Sun et al., 2011
hormone Rat + Shahraki et al., 2008
Serum/plasma parathyroid Rat + Cannata et al., 1983; Díaz-Corte et al., 2001; Gonzelez-Suerez
hormone et al., 2005
Human patient with + Sherrard et al., 1985; Cournot-Witmer and Plachott, 1990
chronic renal failure, on
haemodialysis
Serum thyroid hormone, T4 Rat + Orihuela, 2011
Serum thyroid hormone, T3 Rat + Orihuela, 2011
Serum thyroid hormone, Rat + Orihuela, 2011
free T4
Serum thyrotropin (TSH) Rat + Orihuela, 2011
Insulin Rat + (Acute) + (Chronic) Wei et al., 2018

As an adjuvant, Al in vaccines induces local inflamma-
tion that involves the NLRP3 inflammasome and NLRP3-
independent pathways where macrophages, B- and
T-lymphocytes play important roles in enhancing antigen-
specific immune responses and increasing inflammatory
cytokine production (Exley et al., 2010; Hogenesch, 2013;
Zlatkovic et al., 2013; He et al., 2015). Toxic exposure to Al
causes immunotoxicity leading to inhibition of lympho-
cyte and macrophage functions (Nordal et al., 1988; Zhu
et al., 2014a). Immunosuppression arises from oxidative
stress which is associated with apoptosis of lymphocytes
(Yu et al., 2019) and damage to thymocytes and lympho-
cytes (Kamalov et al., 2011). Immune functions of splenic
B- and T-lymphocytes were inhibited in vitro by reduc-
tion of lymphocyte proliferation, cytokine secretion and
proportions of CD-3(+) and CD-4(+) lymphocytes (She et
al., 2012). LPS-induced NLRP3 inflammasome activation,
IL-1β, IL-6 and TNF-α expression and release in perito-
neal macrophages were also suppressed by Al exposure
(Xu et al., 2018). Norepinerphrine release and activation
of β-adenoceotors/cAMP pathway were promoted by Al
in vivo, and this endocrine factor suppressed macrophage
expressions of MIF and TNF-α (Zhuang et al., 2016).
Contact allergy to Al has been reported as an aberrant
immune response in those having atopic dermatitis
(Netterlid et al., 2013).
The endocrine disruptions or hormonal changes
associated with Al exposure are summarized in Table 2.
Al accumulates in endocrine glands and causes damage
to the glands through oxidative stress, thereby decreas-
ing the level of the hormones secreted (Morrissey et al.,
1983) into the bloodstream for action at the target organs,
causing organ hypofunction. For instance, there are
reports of testicular and ovarian failures (Mohammed
et al., 2008; Fu et al., 2014; Miska-Scramm et al., 2017)
from inadequate androgenic hormone levels (Chinoy and
Patel, 2001; Shahraki et al., 2008; Sun et al., 2011; Muselin
et al., 2016; Mouro et al., 2018) and decreased androgen
receptor functions (Fu et al., 2014; Sun et al., 2018;
Gomes et al., 2019), bone pathology due to dysfunction
of parathyroid gland (Cannata et al., 1983; Sherrard et al.,
1985; Cournot-Witmer and Plachott, 1990; Díaz-Corte et
al., 2001; Gonzelez-Suerez et al., 2005), prediabetes and
diabetes due to pancreatic islet damage (Wei et al., 2018).
Parathyroid function can be impaired by the Al ion act-
ing on calcium-sensing receptors when calcium level is
low, with a higher efficiency than calcium and decreasing
the expression of the receptors in the gland (Gonzelez-
Suerez et al., 2005). The metabolic effect of some levels of
thyroxine (T3 and T4) decline without change in free T4
level is yet to be ascertained (Orihuela, 2011). The secre-
tion of the hormone, sometimes increases when Al ion is
stimulatory to the gland or because the target organs are
refractory or unresponsive to the hormone when there is
receptor depletion or decreased expression of the recep-
tor on the cell membrane. The Al ions act as chemical
stressor by promoting the release of norepinerphrine
(Zhuang et al., 2016) and cortisol (Vasanthan and Joshi,

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54 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
2018); and the elevated levels of these hormones can cause
increase in blood pressure (Zhang et al., 2016). Elevated
blood insulin level is associated with insulin resistance
due to depletion of glucose transporter-4 protein expres-
sion in skeletal muscles during Al exposure (Wei et al.,
2018). Pseudohyperparathyroidism is associated with
osteitis fibrosa in human patients with renal failure and
hypercalcemia when exposed to Al intoxication (Sherrard
et al., 1985).
The cellular membrane is vital for the viability of
the cell and Al exposure disrupts membrane activity
via oxidative stress in various ways. In Alzheimer’s
disease associated with Al exposure, membrane fluidity
increased in platelets and decreased in erythrocytes;
and this observation was corroborated by a study
where in vitro exposure of membrane suspensions to Al
increased fluidity of platelet membranes and decreased
the fluidity of erythrocyte membranes (van Rensburg
et al., 1992) with consequent effect on the viability of
platelets (Neiva et al., 1997) and erythrocytes (Vittori
et al., 2002). Erythrocyte membrane permeability and
osmotic fragility are affected by in vivo and in vitro Al
exposures (Igbokwe, 2018). Erythrocyte osmotic fragil-
ity decreased (Bazzoni et al., 2005) or increased (Zatta
et al., 1989; Hernández et al., 2008; Al-Qayim et al.,
2014; Oztürk and Ozdemir, 2015, Zhang et al., 2016;
Cheng et al., 2018) depending on the Al speciation and
type of erythrocyte injury. Eryptotic (apoptotic) injury
reduces the erythrocyte aggregate size (Bazzoni et al.,
2005) because of the shrinking effect, thereby increasing
osmotic resistance (Igbokwe, 2016). On the other hand,
eryptotic injury which progresses to oncotic injury may
cause swelling of the erythrocyte and increase osmotic
fragility. It is therefore presumed that Al may cause either
shrinking or swelling effect when the erythrocyte mem-
brane is destabilized by Al exposure because of altered
membrane permeability to intracellular and extracellular
ions (Igbokwe, 2016). Cell membrane functions which
regulate transmembrane transport of ions are expected
to be disrupted when ATPase in cell membrane loses
some level of activity during Al exposure. There are
reports showing that Al inhibited activities of Na+K+-
ATPase, Mg2+-ATPase and Ca 2+-ATPase in erythrocytes
(Zhang et al., 2016), vascular endothelial cells (Vorbrodt
et al., 1994), testes (Sun et al., 2018) and ovaries (Fu et al.,
2014) of rats. The Al-induced change in erythrocyte size
may also be accompanied by change in erythrocyte shape
resulting in the formation of echinocytes (Suwalsky et
al., 2004), acanthocytes and stomatocytes (Vittori et al.,
2002) in vitro, due to altered membrane morphology
(Lukyanenko et al., 2013). After long-term oral intake of
Al, schistocytes and target cells were observed in stained
peripheral blood of rats (Vittori et al., 1999). The lipid
bilayer of the plasma and mitochondrial membranes was
morphologically altered in lymphocytes (Skarabahatava
et al., 2015). The protein components of membranes are
degraded or inadequately expressed during Al exposure,
as observed in the loss of band 3 protein of erythrocyte
membrane (Vittori et al., 2002; Vota et al., 2012; Cheng et
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
al., 2018), inaction of membrane-bound enzymes, inhibi-
tion of calbindin protein level in enterocytic membrane
(Cox and Dunn, 2001) and downregulation of GLUT4
protein expression in the membrane of skeletal muscle
(Wei et al., 2018). The surface of cell membranes could
be affected by Al exposure through externalization of
phosphatidylserine after apoptosis (Vota et al., 2012),
inhibition of membrane receptor protein expression in
gonads (Fu et al., 2014; Sun et al., 2018; Gomes et al.,
2019), dysregulation of erythropoietin receptor func-
tions on erythroid progenitors (Vittori et al., 2005) and
loss of membrane surface sialic acid residues on vascular
endothelial tissue with impaired intercellular junctions
(Vorbrodt et al., 1994).
Systemic toxicosis
Pulmonary effect
Pulmonary lesions in humans linked to Al exposure
during production of Al products include granulomatous
pneumonia, pulmonary granulomatosis, pulmonary
fibrosis, pulmonary alveolar proteinosis and desquama-
tive interstitial pneumonia (Chen et al., 1978; Herbert et
al., 1982; Miller et al., 1984; De Vuyst et al., 1987; Jederlinic
et al., 1990; Taiwo, 2014; Iijima et al., 2017). Asthma may
be caused by Al exposure (Burge et al., 2000), though the
asthma among Al workers may be due to other chemical
factors like gases and smoke (Taiwo et al., 2006). Reactive
airways dysfunction syndrome was rarely reported
among Al smelter workers (Wesdock and Arnold, 2014).
Acute-duration oral exposure to Al phosphide has been
reported to cause pulmonary edema in persons following
accidental or volitional ingestion (Chopra et al., 1986;
Khosla et al., 1988). The toxicity was probably due to the
formation of highly toxic phosphine gas rather than to
Al exposure (Alter et al., 2001; Kamanyire and Murray,
2003; Moghadamnia, 2012). Intermediate- and chronic-
duration studies found no organ weight or histological
changes in the lungs of rats exposed to 70 mg Al/kg/day as
Al chloride in drinking water for 30, 60 or 90 days (Dixon
et al., 1979), rats exposed to 133 mg Al/kg/day as Al nitrate
in drinking water for 30 days (Gomez et al., 1986), rats and
mice exposed to 0.6 or 1.2 mg Al/kg/day as Al potassium
sulfate in drinking water for 24 months (Schroeder and
Mitchener, 1975a, b), or mice exposed to 979 mg Al/kg/
day as Al potassium sulfate in food for 20 months (Oneda
et al., 1994). However, Hasseeb et al. (2011) reported
neutrophilic and mononuclear cell infiltrations of lung
alveoli of rats administered 37 mg/kg/day of Al chloride
in drinking water for 8 weeks. Congested blood vessels in
inter-alveolar spaces were reported after administration
of different concentrations of Al chloride via gavage for 8
weeks (Buraimoh and Ojo, 2013). Pulmonary lesions are
rare and inconsistent in experimental animals where Al
exposure is not through aerosol vehicles. Under natural
conditions, the vehicular substances and the Al specia-
tion may influence the stimulation of chronic pathologic
reactions in the lung.

Cardiovascular effects
Toxic myocarditis, myocardial hypokinesia, left ventricu-
lar thrombosis and myocardial dysfunction were reported
in a case of Al phosphide intoxication (Hangouche et al.,
2017). Ischemic stroke due to thrombosis in the right
middle cerebral artery was reported as the delayed
complication of Al phosphide poisoning (Abedini et al.,
2014). However, other Al compounds may not cause car-
diovascular lesion. Cardiac teratogenessis was reported
in embryonic chick heart where defects in ventricular
septation and ventricular myocardium were reported
(El Mazoudy and Bekhet, 2016). There was significant
association between increased maternal hair Al contents
and risk of total congenital heart defects in offspring,
especially in subtypes such as septal defects, conotrun-
cal defects and right ventricular outflow obstruction in
female rats (Wang et al., 2012). No histological changes
were observed in the hearts of rats given 70 mg Al/kg/
day as Al chloride in drinking water for 30, 60, or 90 days
(Dixon et al., 1979). Similarly, no effect on organ weight
nor histological changes were found in the hearts of rats
that ingested 133 or 284 mg Al/kg/day as Al nitrate in
drinking water or base diet for 30 days (Gomez et al.,
1986) or 100 days, respectively (Domingo et al., 1987).
Organ weight and histological changes were not observed
in the hearts of dogs that consumed 75 mg Al/kg/day
(Katz et al., 1984) or 88 mg Al/kg/day (Pettersen et al.,
1990) as sodium Al phosphate in the diet for 6 months.
In summary, cardiovascular effects due to toxicosis are
congenital heart defects, inflammation and dysfunction
of the myocardium and cardiovascular thrombosis.
Gastrointestinal effects
In horses, Al was found in tissues, blood vessel walls and
granulomatous lesions of the intestines associated with
equine granulomatous enteritis (Fogarty et al., 1998),
and Al was demonstrated to have the capacity to induce
granuloma formation in vitro (de Chambrun et al., 2014).
Oral intake of Al may affect the intestinal microbiota,
permeability and immune response which influence the
local inflammatory conditions (Vignal et al., 2016). In
individuals that are genetically susceptible to Crohn’s dis-
ease, Al is linked to the induction and persistence of the
chronic relapsing intestinal inflammation (Lerner, 2007).
Inflammatory bowl diseases, consisting of disease entities
like Crohn’s disease and ulcerative colitis, are character-
ized by excessive intestinal inflammation and experimen-
tal evidence in mice indicates that Al promotes intestinal
inflammation, thereby implicating Al in the pathogenesis
of inflammatory bowl diseases (de Chambrun et al., 2014).
Chemically-induced acute colitis and chronic colitis in
transgenic mice lacking interleukin 10 were aggravated
by oral exposure to Al, because Al increased the intensity
and duration of intestinal inflammation and decreased
regeneration or renewal of the intestinal epithelial
mucosal cells (de Chambrun et al., 2014). Furthermore,
intestinal barrier function was impaired by Al exposure
under basal conditions; and there was a synergistic
stimulation of pro-inflammatory cytokine expression by
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Al and lipopolysaccharides (de Chambrun et al., 2014).
Oral Al chloride exposure caused epithelial degeneration,
goblet cell proliferation and lymphocyte infiltration in the
mucosa of the small intestine of Wistar rats (Buraimoh
and Ojo, 2012). Few experimental studies (Gomez et al.,
1986; Oneda et al., 1994) did not report intestinal lesions
after oral exposure to Al at 133 mg Al/kg/day as Al nitrate
in drinking water to rats for 30 days and 979 mg Al/kg/day
as Al potassium sulfate in the food of mice for 20 months.
The acute and chronic inflammations in the intestine
may induce poor intestinal digestion and absorption.
Hematologic effects
Al exposure has been associated with significant inhibi-
tion of colony forming units-erythroid (CFU-E) develop-
ment in the bone marrow of mice exposed to 13 mg Al/
kg as Al citrate or chloride administered via gavage for
5 days/week for 22 weeks (Garbossa et al., 1996), rats
exposed to 27 mg Al/kg as Al citrate administered via
gavage 5 days/week for 15 weeks (Garbossa et al., 1998),
and rats exposed to 230 mg Al/kg/day as Al citrate in
drinking water for 8 months (Vittori et al., 1999). The
effect of Al on erythroid progenitor cells and erythrocytes
was associated with slow growth and increased degrada-
tion of membrane band 3 proteins, respectively (Vittori
et al., 2002). The genotoxicity from Al exposure in mice
resulted in mitodepressive effect in the bone marrow
(D’Souza et al., 2014). Anemia caused by Al toxicity is
not associated with adequate regenerative activity of
the bone marrow and reticulocytosis (Chmielnicka et
al., 1994; Osman et al., 2012). The additional causes of
anemia appear to be multi-factorial and include defective
hemoglobin production due to inhibition of the enzymes
of heme synthesis, altered erythrocyte membrane struc-
ture and fragility, shortening of red blood cell life span
due to eryptotic and oncotic injuries, and inadequate iron
utilization (Zatta et al., 1989; Perez et al., 2001; Bazzoni
et al., 2005; Vittori et al., 2002; Niemoeller et al., 2006;
Hernández et al., 2008; Sadhana, 2011; Vota et al., 2012;
Lukyanenko et al., 2013; Al-Qayim et al., 2014; Oztürk
and Ozdemir, 2015; Zhang et al., 2016; Cheng et al.,
2018). Significant decreases in hemoglobin, hematocrit
(packed cell volume) and erythrocyte osmotic fragility
were reported after Al exposure (Garbossa et al., 1996;
Garbossa et al., 1998; Vittori et al., 1999; Farina et al.,
2005). The anemia is characterized by decreases in mean
corpuscular volume (microcytosis) and mean corpuscular
hemoglobin (hypochromia), but in chronic exposures,
the erythrocyte parameters recover with persistence of
microcytosis and hypochromia (Mahieu et al., 2000). In
rats loaded with Al, heme dyshomeostasis was reported
with evidence of decreased activity of aminolevulinic acid
dehydratase and increased activity of heme oxygenase in
the rat liver associated with activation of JNK pathway,
indicating an increase in heme degradation (Lin et al.,
2013). No alterations in hemoglobin, hematocrit and
erythrocyte osmotic fragility were reported in a number
of experimental Al exposures (Katz et al., 1984; Gomez
et al., 1986; Domingo et al., 1987; Pettersen et al., 1990;
56 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
Table 3. Summary of haematologic effects of aluminium toxicosis.
Toxic effects Toxic actions
Depressed Inhibition of CFU-E
erythropoiesis
Slow growth of erythroid cells
Inhibition of heme synthesis
Increased heme degradation
Dysregulated erythropoietin receptor function
Anaemia Reduced erythrocyte life span
Erythrocyte apoptosis (eryptosis)
Altered erythrocyte fragility
Decreased erythrocyte membrane fluidity
Inhibition of erythrocyte membrane ATPase
Altered erythrocyte shape: echinocytes,
acanthocytes, stomatocytes, target cells
Oteiza et al., 1993b; Garbossa et al., 1996). Vittori et
al. (1999) did not find significant alterations in plasma
iron levels or total iron binding capacity in rats exposed
to 230 mg Al/kg/day as Al citrate in drinking water for
8 months; however, they reported impaired iron uptake
and decreased iron incorporation into heme in the bone
marrow. Farina et al. (2005) found significant decreases
in blood iron concentrations and no change in total iron
binding capacity in rats exposed to 54.7 mg Al/kg/day as
Al sulfate in a sodium citrate solution in drinking water
for 18 months. Florence et al. (1994) reported decreases
in serum iron levels, total iron binding capacity, and
transferrin saturation in rats exposed to 75 mg Al/kg/day
as Al citrate in the diet for 6 months. Chronic Al exposure
in rats disrupted iron homeostasis (Zhang et al., 2010). In
summary, the hematologic effect of toxicosis consists of
anemia due to erythrocyte and erythroid pathology with
suppression of erythropoiesis (Table 3)
Neurologic effects
In humans, Al accumulation in the brain and scalp hairs
has been associated with neurodegenerative diseases such
as dialysis-associated encephalopathy, Alzheimer’s dis-
ease, Parkinson’s disease (dementia), amyotropic lateral
sclerosis, multiple sclerosis and autism (King et al., 1981;
Savory et al., 1996; Kawahara and Kato-Negishi, 2011;
Arain et al., 2015; Jones et al., 2017; Mirza et al., 2017;
Mold et al., 2018). The Al in brains of 5 out of 12 donors
with familial Alzheimer’s disease was > 10 µg/g dry weight
(Mirza et al., 2017). In autism, Al in parts of the brain was
up to 19 µg/g dry weight (Mold et al., 2018). There is a role
for Al in multiple sclerosis because patients excrete high
amounts of Al in urine, facilitated by drinking silicon-rich
mineral water (Jones et al., 2017). Subchronic exposure
to Al was associated with reduced population of neural
stem cells and hampered cell proliferation and neuroblast
differentiation in the brain of mice (Nam et al., 2014,
2016). Injection of Al, especially intra-cisternally, induced
neurological changes in animal models (Wisniewski et al.,
1980; Anon, 2008c). Rats orally administered Al (100 mg/
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
kg/day) for 90 days accumulated more Al in their brains,
had increased brain acetyl cholinesterase activity and had
decreased brain choline acetyltransferase activity (Bilkei-
Gorzó, 1993). Mice fed high Al levels (1,000 mg/kg diet
of Al as Al lactate) were less active, had decreased grip
strength, and increased startle responses after 90 days
when compared with control (Golub et al., 1992). Oteiza
et al. (1993b) reported that mice fed diets containing
1,000 mg/kg diet of Al (as Al chloride) with sodium citrate
accumulated more Al in the brain nuclear fraction and
spinal cord, had lower grip strength, and greater startle
responsiveness after 5 and 7 weeks. Old (18 months of
age) rats exposed to Al (100 mg/kg/day) in drinking water
with citrate (356 mg/kg/day of citrate) had decreased
numbers of synapses and a greater percentage of perfo-
rated synapses than controls, but no changes in behavior
(Colomina et al., 2002). Garruto et al. (1989) reported that
cynomolgus monkeys fed a low calcium diet (3,200 mg/
kg diet) with Al (125 mg/day) for 41 to 46 months had
more degenerative changes that were consistent with
early Alzheimer’s disease or Parkinson’s dementia in the
central nervous system than control monkeys. Golub and
Germann (2001) observed growth depression and poorer
performance on standardized motor tests in mice off-
spring when dams were exposed to Al (1,000 mg/kg diet as
Al lactate) with marginal levels of calcium and magnesium
during pregnancy and lactation. Mice fed lower rather
than recommended levels of calcium (2,500 versus 5,000
mg/kg diet of calcium) with Al (15,600 mg/kg diet as Al
hydroxide) for 11 to 25 months accumulated more hyper-
phosphorylated tau protein in the cortical neurons and
had more atrophic neurons in the central nervous system
(Kihira et al,. 2002). Transgenic mice with over-expressed
human amyloid precursor protein had increased brain
isoprostane levels and more amyloid-β peptide formation
and deposition when Al was added to their diets, but the
effects of Al were reversed by additional dietary vitamin E
(Pratico et al., 2002), suggesting that Al could contribute
to neurodegeneration by enhancing amyloid deposition
and aggravating lesions by oxidative events (Campbell and
Bondy, 2000; Yuan et al., 2012; Chen and Zhong, 2014;
Liaquat et al., 2019). In a nutshell, Al exposure promotes
oxidative stress and amyloid deposition in the nervous tis-
sue which results in neurodegeneration, neuronal necrosis
and dysneurogenesis, which constitute the basis for the
neurological diseases associated with Al intoxication.
Musculoskeletal effects
The major myopathy induced by Al exposure is macro-
phagic myofasciitis (aluminic granuloma) associated
with chronic arthromyalgia or myalgia and chronic
fatigue syndrome (Exley et al., 2009; Gherardi and
Authier, 2012; Rigolet et al., 2014; Gherardi et al., 2016;
Miller, 2016). Skeletal muscle necrosis occurred in the
diaphragm and abdominal muscles of rats adjacent to the
peritoneum after intraperitoneal injection of Al lactate
(Levine et al., 1992). Muscle fiber atrophy, with retarda-
tion of growth, was reported in growing pigs which was
associated with hypophosphatemia induced by dietary Al

hydroxide supplementation (Haglin et al., 1994). Smooth
muscle contraction induced by K+ ion was inhibited by Al
exposure (Nasu et al., 1998). Myocardial function may be
altered in diabetic individuals by Al exposure, in as much
as Al toxicity potentiates the decline in calcium uptake
into the sarcoplasmic reticulum of the myocardial fibers
of such individuals (Levine et al., 1990). In individuals
where neurodegerative conditions affect the nerve supply
to muscles, the muscles may undergo denervation atro-
phy and become dysfunctional as in multiple sclerosis or
amyotropic lateral sclerosis. Taken together, Al toxicosis
may cause muscle damage, inflammation and dysfunction
The bone diseases associated with Al exposure are
osteoporosis, osteomalcia, rickets, exostosis, osteodystro-
phy and osteitis fibrosa (Sherrard et al., 1985; Chappard et
al., 2016; Rodríguez and Mandalunis, 2018; Klein, 2019).
There is increased risk of osteoporosis and low bone min-
eral density during Al exposure (Cao et al., 2016; Sun et al.,
2016) because of disruption of bone formation, and inhibi-
tion of osteoblast proliferation, differentiation and miner-
alization (Li et al., 2012, 2016; Cao et al., 2016; Sun et al.,
2016; Yang et al., 2016; Zhu et al., 2016b; Song et al., 2017;
Sun et al., 2017; Huang et al., 2017). In individuals with Al
overload, undecalcified bone matrix contains Al and bone
conditions like exostosis and osteomalacia may occur in
circumstances that increase Al uptake and colocalization
as observed in celiac disease, hemochromatosis and sickle
cell anemia (Chappard et al., 2016). Osteoclastogenesis is
promoted by low-dose exposure while osteoclast apoptosis
is caused by high-dose exposure (Yang et al., 2018). There
are case reports of osteomalacia and rickets in infants
and adults using Al-containing antacids for the treat-
ment of gastrointestinal illnesses (Chines and Pacifici,
1990; Pivnick et al., 1995; Woodson, 1998). The Al in
antacids binds with dietary phosphorus and prevents its
absorption resulting in hypophosphatemia and phosphate
depletion (Woodson, 1998). Osteomalacia, characterized
by bone softening, increased spontaneous fractures and
pain, has been reported in dialyzed uremic adults and
children exposed to Al-contaminated dialysate or orally
Figure 7. Pathogenesis of bone disease in aluminium toxicosis.
Copyright © 2019 SETOX & Institute of Experimental Pharmacology and Toxicology, CEM SASc.
Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 57
Full-text also available online on PubMed Central
administered Al-containing phosphate-binding agents
(Mayor et al., 1985; Wills and Savory, 1989; Andreoli,
1990). Low osseous remodeling rate and peripheral
resistance to parathyroid hormone are associated with
Al intoxication (Pun et al., 1990). Decreased Al urinary
excretion caused by impaired renal function with, possi-
bly, an increase in gastrointestinal absorption of Al results
in increased Al load leading to markedly increased bone
Al levels and the presence of Al between the junction of
calcified and non-calcified bones (Alfrey, 1993). Long-
term oral exposure to Al results in an increase in Al levels
in the bone (Ahn et al., 1995; Konishi et al., 1996) that is
responsible for the bone disease.
In brief, the review has identified the following events
to occur during Al exposure to disrupt bone morphol-
ogy: (a) interference with the availability of calcium for
bone formation at the level of intestinal absorption and
hormonal control through parathyroid hormone; (b) inhi-
bition of osteoid formation and mineralization through
osteoblast dysregulation; and (c) destabilization of osteo-
clast functions with alteration in osteoclastogenesis and
osteoclast apoptosis (Figure 7).
Reproductive and developmental effects
Human reproduction may be affected negatively by Al
exposure (Klein et al., 2014; Mouro et al., 2017). Human
semen and spermatozoa contain Al and patients with
oligospermia had higher Al concentration than healthy
individuals (Klein et al., 2014). At human dietary level
of Al and continuous exposure for 60 days, the rat testes
accumulated low Al levels of 3.35 µg/g and it was associ-
ated with increased oxidative stress and inflammation,
decreased daily sperm production, reduced sperm count
and motility and increase in abnormal spermatozoa
(Martinez et al., 2017). In male rats, subchronic exposure
to Al chloride did not result in elevated Al accumula-
tion in the testes, but toxic effects reported in the testes
included impairment of spermatogenesis and increase in
sperm malformation rate (Zhu et al., 2014b). Imbalance
in trace mineral metabolism occurred in the testis with
58 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
testicular levels of iron and zinc increasing and that of
copper decreasing during exposure (Zhu et al., 2014b).
Furthermore, metabolic inhibition in the testis was
reported with regard to the functions of acid phospha-
tase, succinate dehydrogenase, and lactate dehydroge-
nase and its isoenzymes (Zhu et al., 2014b), alongside
with testicular membrane dysfunction due to inhibition
of membrane ATPase activities in Al-exposed rats (Sun
et al., 2018). The weights of the testes and epididymides
were decreased by Al exposure in rats as serum testos-
terone levels dropped (Mouro et al., 2018). In male rats,
testicular development was impaired by Al exposure,
associated with reduction in serum levels of testosterone
and luteinizing hormone (LH) levels and decrease in
androgen receptor protein expression without effect on
serum follicle stimulating hormone (FSH) (Sun et al.,
2011, 2018). The offspring of exposed rats (F0) in a three-
generation study belonging to F1 and F2 had decreased
testosterone and LH levels, decreased testicular weight,
and increase in the production of abnormal immobile
spermatozoa, whereas the parental F0 group did not
present with such reproductive abnormalities (Muselin
et al., 2016). In rats that were injected with Al chloride
(4.125 pmole) in artificial cerebrospinal fluid via the lat-
eral ventricle, there were significant decreases in serum
FSH, LH and testosterone levels, and reduction in sperm
count from the vas deferens and epididymides (Shahraki
et al., 2008). Bank voles (Myodes glareolus) exposed to
Al produced lower quality and quantity of sperm than
normal, but reproductive capacity was not significantly
affected in females (Miska-Schramm et al., 2017). After
intraperitoneal treatment at 50 mg/kg for 20 days, blood
testosterone and LH levels were increased in male rats,
but FSH level was not affected (Resa and Palan, 2006).
Khattab et al. (2010) reported that administration of Al
chloride (20 mg/kg) to male rats via gavage for 70 days
caused fertility disturbances and testicular dysfunction.
Other reports showed that Al induced decrease in sperm
counts, motility and viability, with increase in dead and
abnormal sperm counts (Bataineh et al., 1998; Guo et
al., 2005; Yousef et al., 2007; Yousef and Salama, 2009;
Figure 8. Reproductive and developmental disorders in aluminium toxicosis.
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
D’Souza et al., 2014). Testicular and epididymal weights
and serum testosterone and luteinizing hormone levels
were reduced by Al exposure (Reza and Palan, 2006;
Mouro et al., 2017). In male and female gerbils (Meriones
unguiculatus), Al exposure disrupted prostate develop-
ment in neonates, with the consequence of adult off-
spring having elevated serum testosterone levels with low
androgen receptor frequency associated with increased
proliferation of cells of the prostate (Gomes et al., 2019).
Chinoy and Patel (2001) exposed female mice to Al
chloride at 200 mg/kg for 30 days and observed decreased
steroidogenesis in the ovaries associated with decreased
serum estradiol levels. Exposure to Al sulphate during
gestation caused reduction in maternal body weight,
reduction in fetal weight and crown rump length, and
impairment of fetal bone development and preossifica-
tion (Yassa et al., 2017). In adult mice exposed to Al at
1000–1400 ppm in drinking water or 19–39 mg/kg intra-
peritoneally, pregnancy rate decreased with increased
frequency of atretic follicles; after pregnancy, failure
of pregnancy increased with increased rate of uterine
resorption and decrease in the number of viable fetuses
and implantation sites (Mohammed et al., 2008). Fu et al.
(2014) reported that Al exposure damaged ovarian struc-
ture, disrupted metabolism of iron, zinc and copper in the
ovary and decreased the activities of ovarian ATPases and
expressions of androgenic receptors for FSH and LH; and
could consequently lead to infertility due to inhibition of
ovulation and development of corpus luteum. Exposure
to Al during mouse pregnancy resulted in reduced fetal
weight and increased frequency of external anomalies in
fetuses (Malekshah et al., 2005) and fetal micronucleated
erythrocytes (D’Souza et al., 2014). Khalaf et al. (2007)
reported perinatal and postnatal adverse effects of Al
exposure on fetuses and neonates during gestation and
lactation of female rats. The hepatic toxicity of Al chloride
was also reported in pregnant rats and their offspring
with observation of decreased fetal weight and size
(Mestaghanmi et al., 2003). Exposed embryonic chicks
and rat fetuses developed congenital myocardial defects
(Wang et al., 2012; El Mazoudy and Bekhet, 2016).

On the whole, Al toxicosis caused lesions in the testes
and ovaries resulting in impairment of spermatogenesis
and ovarian function related to ovulation, with the con-
sequence of reproductive inefficiency associated with
pregnancy failures and poor fetal development (Figure 8).
Hepato-renal and pancreatic effects
Al causes oxidative injuries to the kidney and liver leading
to tissue degeneration and necrosis, and associated serum
biochemical derangements (Nikolov et al., 2010; Mailloux
et al., 2011; Bai et al., 2012; Li et al., 2015; Xu et al., 2017).
Abdel-Wahab (2012) reported a significant increase
in the activities of alanine aminotransferase (ALT),
alkaline phosphatase (ALP), aspartate aminotransferase
(AST) and total bilirubin, as well as increased serum
urea and creatinine levels after oral administration of
20 mg/kg of Al chloride for 30 days in experimental rats.
Ingestion of aluminium phosphide pellets was reported
to induce acute pancreatitis in one patient (Verma et al.,
2007). Rats had moderate pancreatic islet necrosis after
intermediate oral exposure (50 mg/kg for 28 days) to Al
chloride (Figure 9) which was associated with impaired
fasting blood glucose and impaired oral glucose toler-
ance (Igwenagu, 2017; Igwenagu et al., 2019). Rats treated
intra-peritoneally with Al chloride at 10 mg/kg for 30
days had significantly increased fasting blood glucose,
serum insulin level and insulin resistance index on days
10 and 20 of treatment, but as treatment progressed to
day 30, serum insulin level had decreased, indicating that
pancreatic β-cell function decreased as pancreatic dam-
age occurred with progression of treatment (Wei et al.,
2018). The hepatic and pancreatic lesions cause changes
in metabolism (Figure 5) which result in hyperglycaemia,
hypoproteinaemia, hyperlipidaemia, hypercholester-
olaemia and hypertriglyceridaemia (Omar et al., 2003;
Kowalczyk et al., 2004; Türkez et al., 2011; Abdel-Wahab,
2012; Belaïd-Nouira et al., 2013).
Mammary gland or breast effects
Breast cancers and cysts are mammary gland conditions
where emerging evidence are suggesting that Al may be
involved in their causation (Darbre, 2016). Al chlorohy-
drate in antiperspirant cosmetics and other underarm
cosmetic products may be an important source of Al
exposure (Pineau et al., 2014; Linhart et al., 2017). In a
case control study (Linhart et al., 2017), the use of under-
arm cosmetic products containing Al was significantly
associated with breast cancer incidence and the Al levels
in breast tissues were significantly higher in breast cancer
cases than controls (5.8 versus 3.8 nmol/g). Breast cancer
patients had higher levels of Al in breast tissues than in
blood serum (Darbre et al., 2013b). There were higher
levels of Al in nipple aspirates of cancer patients than
healthy controls and higher Al levels in breast cyst fluid
than serum or milk (Darbre et al., 2011). The Al contents
of nipple aspirates of breast cancer patients correlated
with biomarkers of oxidative stress and inflammation
in the breast microenvironment (Mannello et al., 2013).
The Al accumulating in the breast tissue may influence
Copyright © 2019 SETOX & Institute of Experimental Pharmacology and Toxicology, CEM SASc.
Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 59
Full-text also available online on PubMed Central
Figure 9. Photomicrograph of pancreas of aluminium chloride-
treated rat showing coagulative necrosis of the pancreatic islet
tissue with disorganization of its architecture (H & E, x 400) From
Igwenagu et al. (2019).
the biological characteristics of breast epithelial cells
and carcinogenesis is considered a probable outcome
(Pineau et al., 2014). The content of Al in breast tissues
from mastectomies are being efficiently and accurately
estimated in order to properly assess the involvement of
Al in the aetiology of breast cancer (House et al., 2013).
Current evidence suggests that Al can induce DNA dam-
age in human breast epithelial cells and subsequently
induce proliferation of the cells (Darbre et al., 2013a, b).
Thus, Al may increase the risk of breast cancer by act-
ing as a metalloestogen (Darbre, 2016). The migratory
and invasive properties of oestogen-responsive MCF-7
human breast cancer cells were increased in the pres-
ence of Al (Darbre et al., 2013a). Long-term Al exposure
also increased the migration of oestrogen-unresponsive
MDA-MB-231 human breast cancer cells in culture where
their expression of matrix metalloproteinases (MMP9/14)
was increased (Bakir and Darbre, 2015).
Diagnosis and treatment of
aluminium intoxication
Al can be measured in the blood, bone, urine, and feces to
confirm Al load and association with toxicosis. A variety
of analytical methods have been used to measure Al
levels in biological materials and they include accelerator
mass spectroscopy, graphite furnace atomic absorption
spectrometry, flame atomic absorption spectrometry,
electro-thermal atomic absorption spectrometry, neutron
activation analysis, inductively coupled plasma atomic
emission spectrometry, inductively coupled plasma mass
spectrometry, and laser microprobe mass spectrometry
(Maitani et al., 1994; Owen et al., 1994; Van Landeghem
et al., 1994; Razniewska and Trzcinka-Ochocka, 2003).
Contamination is a major problem encountered in the
60 Aluminium toxicosis
Ikechukwu Onyebuchi Igbokwe, Ephraim Igwenagu, Nanacha Afifi Igbokwe
analysis of Al by all methods except that using radioactive
26Al. When using the other methods, all items used dur-
ing collection, preparation, and assay should be checked
for Al contribution to the procedure.
Treatment of Al intoxication is done with the chelat-
ing agent, deferoxamine, which is a colourless crystalline
base, produced by the bacterium, Streptomyces pilosus.
Structurally, it is composed of one molecule of acetic
acid, two molecules of succinic acid and three molecules
of 1-amino-5 hydroxylamine pentane (Keberle, 1964).
Deferoxamine is mainly used as an iron-chelating agent
to treat iron overload. But due to the chemical similar-
ity between Al and iron, it can also successfully mop-up
excess Al from the body (Day, 1986; Martin et al., 1987).
Deferoxamine administered intravenously has been
shown to reduce the body Al load and to ameliorate injury
to the bone and brain in patients receiving hemodialysis
and peritoneal dialysis (Malluche et al., 1984). It has also
been used successfully to treat Al toxicity in children
(Warady et al., 1986; Ogborn et al., 1991). Deferoxamine
therapy seems beneficial for those with established Al
toxicity; however, this therapy is not without hazards.
It may cause allergic reactions such as pruritus, wheals
and anaphylaxis. Other adverse effects include dysuria,
abdominal discomfort, diarrhea, fever, leg cramps, cata-
ract, and tachycardia (Klaassen, 1990).
Malic acid is also a potent chelator of Al used in treat-
ment of Al intoxication (Domingo et al., 1988). Treatment
with malic acid has been reported to greatly increase
the fecal and urinary excretion of Al and reduce the
concentration of Al present in various organs and tissues
(Rim, 2007; Crisponi et al., 2012; Al-Qayim et al., 2014).
Other chelating agents such as citric, malonic, oxalic, and
succinic acids have been used experimentally to reduce
aluminum load in rats and mice (Domingo et al., 1988).
Antioxidants and free radical scavengers such as
selenium, melatonin, boric acid and vitamin C have been
employed experimentally to ameliorate the deleteri-
ous effects of free radicals produced as a result of Al
Figure 10. Prevention and treatment of aluminium toxicosis.
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
intoxication (Omar et al., 2003; Abubakar et al., 2004;
Fyiad, 2007; Turkez et al., 2011). Other researchers have
used plant extracts of fenugreek seed, grape seed, ginger,
wheat grass powder, black tea, Allium cepa, Caesalpinia
crista, Arthrophytum (Hammada scoparia), Moringa
oleifera and Celastrus paniculatus to ameliorate the toxi-
cosis caused by Al exposure (Khattab et al., 2010; Hasseeb
et al., 2011; Osman et al., 2012; Belaïd-Nouira et al., 2013;
Sumathi et al., 2013; Bitra et al., 2014; Osama et al., 2014;
Mathiyazahan et al., 2015; Singh and Goel, 2015; Taїr et
al., 2016; Ravi et al., 2018). The neuronal death in the hip-
pocampus of the brain associated with neurodegeneration
in rats caused by Al exposure was attenuated by quercetin
(Sharma et al., 2016). Ginsenoside Rb1 was reported
to prevent Al-induced oxidative stress and reverse the
osteoblast viability and growth after impairment by Al
(Zhu et al., 2016a). Chlorogenic acid was effective as a
chelating agent and antioxidant in protection against the
toxicity of Al (Wang et al., 2018; Cheng et al., 2017, 2019).
Chenodeoxycholic acid ameliorated the neurotoxic effect
of Al by improving insulin sensitivity (Bazzari et al., 2019).
Türkez et al. (2010) reported that propolis prevented the
genetic and hepatic damages induced by Al intoxication.
On the whole, the approach to the treatment of Al toxi-
cosis after diagnosis involves strategies that include the
following: prevention of Al intake, reduction of Al absorp-
tion, increasing Al excretion, maintaining functional kid-
neys, reducing Al load by chelation with chelating agents
and amelioration of toxic effects with antioxidants and
other agents that reduce toxicity (Figure 10)
General perspective and conclusion
This review has provided an overview of the pathologic
basis of Al toxicosis. The association of Al intoxications
with various pathologic syndromes and pathogenic
mechanisms linked to toxic actions may provide avenues
for strategic interventions. The study of these pathologies

have received recent attention in epidemiological surveys
in regard to some human diseases such as Alzheimer’s
disease, autism, osteoporosis, diabetes mellitus, inflam-
matory bowel disease and others mentioned in the
review. We have reviewed the process of Al intoxication,
toxic actions and systemic effects with an exploratory
approach to provide the subsequent highlights of the
review in this section.
After the intake of Al and its deposition in tissues,
the cell is the primary target of the toxic action of Al,
where the ion interacts with the plasma membrane
moieties, cytoplasmic biomolecules, mitochondria
and nuclear structures. The major toxic action of Al is
to generate oxidative stress by producing reactive free
radicals which can overwhelm the antioxidant defenses
of the cell to perpetrate cellular injuries. The oxidative
injuries emanate from the oxidation of proteins, lipids
and nucleotides, which result in generation of altered
functional biomolecules with defective operational
capabilities towards cellular homeostasis. The disrup-
tion of homeostatic environments of the cell has the
capacity to change the semi-permeability and receptor
functions of the plasma membrane, alter the reactivity of
metabolic intermediary molecules and the functions of
enzymes and cofactors, and breach the energetic profile
and synthetic infrastructure at transcriptional and post-
transcriptional stages. In Al toxicosis, we identified the
inhibition of cellular viability and function of neurons,
osteoblasts, endocrine cells, lymphocytes, macrophages,
erythrocytes, erythroid cells, enterocytes, myocytes,
germinal cells, and pulmonary alveolar, hepatic, renal
and pancreatic islet cells. Progenitor or blast cells were
not able to proliferate, differentiate and function in
accordance with their genetic resources. The secretory
functions of specialized cells were impaired and several
signaling pathways were recruited in abnormal chemico-
biological settings. Cytokine expression was accelerated
by oxidative cellular injuries to initiate inflammatory
processes and alter immune responses that support
inflammation and immunosuppression, respectively.
There were Al-induced endocrine disruptions and altered
sensitivities to hormones such as insulin, parathyroid
hormone and hormonal vitamin D.
In Al toxicosis, the cellular structures were damaged
by molecular mechanisms which cause degenerative
changes (from lipid and amyloid depositions), cell death
by apoptosis or necrosis, and dysplasia from genetically
driven cell growth abnormalities. Cellular degeneration
occurred in nervous tissue, liver and kidney. Apoptosis
was associated with damage to immune cells, erythroid
cells, erythrocytes, osteoblasts and germinal cells.
Necrosis was encountered in pancreatic islet, liver, kid-
ney, neurons and muscles. Dysplasia from chromosomal
aberrations was associated with developmental defects,
teratogenesis and growth abnormalities in fetuses and
mammary epithelial cells. Mutagenesis, cell prolif-
eration and impaired mitosis in Al toxicosis are gray
areas requiring clarification because of the observed
antithesis.
Copyright © 2019 SETOX & Institute of Experimental Pharmacology and Toxicology, CEM SASc.
Interdisciplinary Toxicology. 2019; Vol. 12(2): 45–70 61
Full-text also available online on PubMed Central
The systemic effects caused by Al toxicosis are diverse
and multifaceted, but co-morbidities from multisystemic
toxicosis are rarely reported in epidemiological cohorts.
The convergence of toxic actions to engage multiple organ
systems in an individual is often an observation in experi-
mental animal models and lacks validity in observational
studies in human or animal populations. The possible
action of Al in the pathogenesis of diabetes mellitus and
the concurrence of neurological disorders associated with
Alzheimer’s disease and other dementias (Arnold et al.,
2018) point to the common cellular basis of the patho-
genesis of both metabolic and cognitive disorders, which
can arise from toxic actions of Al. Longitudinal studies in
the future may reveal co-morbidities and multisystemic
toxicosis in Al-loaded individuals in locations where there
is high risk of Al exposure.
Al-induced oxidative stress with the metabolic defects
that accompanies it may incidentally be the crux of the
toxicosis, to the extent that the use of antioxidant agents
forms the fundamental basis for therapeutic interven-
tions apart from chelating drugs. Chenodeoxycholic acid
improved insulin sensitivity to ameliorate the neurotoxic
effect of Al (Bazzari et al., 2019). As new researches on
the cellular mechanisms in the toxicosis continue to be
further elucidated through in vitro and in vivo studies of
the metallic toxicant, new therapies against the toxicosis
should also focus on alleviating the known aberrations
in signaling pathways, synthetic and secretory functions,
cellular energetics and membrane integrity.
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